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Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides

Abstract

Understanding how catalytic asymmetric reactions with racemic starting materials can operate would enable new enantioselective cross-coupling reactions that give chiral products. Here we propose a catalytic cycle for the highly enantioselective Rh(i)-catalysed Suzuki–Miyaura coupling of boronic acids and racemic allyl halides. Natural abundance 13C kinetic isotope effects provide quantitative information about the transition-state structures of two key elementary steps in the catalytic cycle, transmetallation and oxidative addition. Experiments with configurationally stable, deuterium-labelled substrates revealed that oxidative addition can happen via syn- or anti-pathways, which control diastereoselectivity. Density functional theory calculations attribute the extremely high enantioselectivity to reductive elimination from a common Rh complex formed from both allyl halide enantiomers. Our conclusions are supported by analysis of the reaction kinetics. These insights into the sequence of bond-forming steps and their transition-state structures will contribute to our understanding of asymmetric Rh–allyl chemistry and enable the discovery and application of asymmetric reactions with racemic substrates.

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Fig. 1: Suzuki–Miyaura cross-coupling.
Fig. 2: Examining the transmetallation step using experimental and computational techniques.
Fig. 3: Examining the 13C KIE.
Fig. 4: A condensed Gibbs energy profile showing transmetallation, oxidative addition and reductive elimination.
Fig. 5: Asymmetric allylic arylation with heterocyclic allyl chlorides.
Fig. 6: Asymmetric allylic arylation with deuterium-labelled allyl chlorides and diastereomeric allyl chlorides.
Fig. 7: Simplified models showing the origins of diastereoselectivity and enantioselectivity in this Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling.

Data availability

Detailed experimental methods and analytical data for all the experiments, along with absolute energies and selected distances for the DFT-computed structures and for the computed stationary points, can be found in the Supplementary Information. Cartesian coordinates (in xyz format) for the computed stationary points can be found in the Supplementary Data.

Code availability

All Python scripts used for the data analysis have been made available at https://github.com/bobbypaton under a creative commons CC-BY license.

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Acknowledgements

The EPSRC supports this work though standard grant EP/N022246/1. L.v.D. and R.A. thank the EPSRC Centre for Doctoral Training (CDT) in Synthesis for Biology and Medicine (EP/L015838/1) for studentships, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex. R.A. also acknowledges the Development and Promotion of Science and Technology Talents Project and the Royal Thai Government. This material is based on work supported by the National Science Foundation under Grant no. 1955876. We used the Dirac cluster at Oxford supported by the EPSRC CDT for Theory and Modelling in Chemical Sciences (EP/L015722/1), the RMACC Summit supercomputer, which is supported by the National Science Foundation (ACI-1532235 and ACI-1532236), the University of Colorado Boulder and Colorado State University, and the Extreme Science and Engineering Discovery Environment (XSEDE) through allocation TG-CHE180056 and computing resources provided by the National e-Science Infrastructure Consortium, Thailand. O.S. thanks the Scientific and Technological Research Council of Turkey for the 2214-A Scholarship Programme. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. [838616].

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S.P.F. conceived and directed the project. S.P.F., L.v.D. and M.S. designed the experiments. L.v.D., M.S. and S.K. performed the experiments. L.v.D., R.A., M.S., R.S.P., G.C.L.-J. and S.P.F. analysed the experimental results. R.S.P, L.v.D., R.A. and O.S. designed, conducted and analysed the computational work. T.D.W.C. designed and performed the 13C NMR experiments. G.C.L.-J. derived the pseudo steady-state rate equation. L.v.D. and S.P.F. wrote the manuscript with contributions from R.S.P., G.C.L.-J., T.D.W.C., M.S. and R.A.

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Correspondence to Timothy D. W. Claridge or Guy C. Lloyd-Jones or Robert S. Paton or Stephen P. Fletcher.

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Peer review information Nature Catalysis thanks Per-Ola Norrby and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–8, Tables 1–26, Methods, Discussion and References.

Supplementary Data

Co-ordinates of computed structures in xyz format.

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van Dijk, L., Ardkhean, R., Sidera, M. et al. Mechanistic investigation of Rh(i)-catalysed asymmetric Suzuki–Miyaura coupling with racemic allyl halides. Nat Catal 4, 284–292 (2021). https://doi.org/10.1038/s41929-021-00589-y

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